Method for control of hyperlipidemia

ABSTRACT

The present invention is directed to a method of controlling hyperlipidemia in mammals which comprises administering to a mammal an amount effective to control hyperlipidemia of a compound having hypolipidemic activity and the structural formula: ##STR1## wherein R 1  is hydrogen, a C 1  to C 18  alkyl or substituted alkyl, a C 2  to C 18  alkenyl or substituted alkenyl, a C 2  to C 18  alkynyl or substituted alkynyl, a C 4  to C 10  cycloalkyl or substituted cycloalkyl, a C 4  to C 10  cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, --CO--R 9  or --Y--CO--R 9  ; 
     R 2  is ##STR2## R 3  and R 4  can be the same or different and are each the same as R 1  ; 
     R 5 , R 6  and R 7  can be the same or different and are each hydrogen, a C 1  to C 18  alkyl or substituted alkyl, a C 2  to C 18  alkenyl or substituted alkenyl, a C 1  to C 18  alkynyl or substituted alkynyl, a C 4  to C 10  cycloalkyl or substituted cycloalkyl, a C 4  to C 10  cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R 9 , or --Y--CO--R 9 , 
     with the proviso that R 5  and R 6  together cannot be so bulky as to cause the compound to decompose; 
     R 8  is hydrogen, a C 1  to C 5  alkyl, a C 4  to C 10  cycloalkyl, --CO--R 9  or Y--CO--R 9  ; 
     R 9  is hydrogen, a C 1  to C 5  alkyl or substituted alkyl, a C 2  to C 5  alkenyl or substituted alkenyl, a C 2  to C 5  alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C 1  to C 5  alkoxy or substituted alkoxy, a C 4  to C 10  cycloalkyl or substituted cycloalkyl, a C 4  to C 10  cycloalkenyl or substituted cycloalkenyl, --NHC 6  C 5l  , --NR 10  R 11  wherein R 10  and R 11  can be the same or different and are each hydrogen, a C 1  to C 5  alkyl or substituted alkyl, phenyl or substituted phenyl; 
     Y is a C 1  to C 10  alkylene or substituted alkylene; R 12  is --CO, --COH, --CS, --CSH, or a C 1  to C 4  alkylene group; and 
     and the pharmaceutically acceptable salts, and mixtures thereof.

FIELD OF THE INVENTION

The present invention relates to compositions having hypolipidemic activity and methods for their use in controlling hyperlipidemia in mammals. Specifically, the present invention is directed to methods for controlling hyperlipidemia by treating mammals, especially humans, with a class of hypolipidemic agents selected from 1,2,4-triazolidine-3,5-diones, 1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones and 1,3,5-triazine-2,4(1H,3H)-diones.

BACKGROUND OF THE INVENTION

Cholesterol is commonly found in all the tissues and blood of mammals, especially humans. Manufactured in the liver and other cells as a substrate for other steroids and membrane synthesis; cholesterol is a normal constituent of bile. As will be appreciated, many familiar foods contain cholesterol, with some containing more than others. Maintaining proper levels of cholesterol in the body has become an important factor in todays diet, since medical science has proven that certain afflictions such as hypothyroidism, diabetes and the intake of foods having a high cholesterol content may result in high levels of cholesterol in the blood.

A condition which is associated with elevated levels of cholesterol, phospholipids, and/or triglycerides in the blood serum of mammals is commonly referred to as hyperlipidemia (i.e. as used herein, reference to hyperlipidemia is intended to be inclusive of both hypercholesterolemia and hypertriglyceremia, and hence, compounds having a hypolipidemic effect will exhibit activity to lower both cholesterol and triglyceride lipid levels). Hyperlipidemia can lead to serious health problems such as arthereosclerosis. We know that serum lipoprotein in mammals is composed of cholesterol together with triglyceride, phospholipid and apoproteins. Lipoprotein is composed of several fractions--the very low density lipoprotein (VLDL), the low density lipoprotein (LDL) and the high density lipoprotein (HDL) depending on the specific gravity of the apoprotein components of the fraction. Medical evidence points to the VLDL and LDL fractions as being associated with atherosclerosis. In contrast, the HDL fraction appears to carry cholesterol from the blood vessels to the liver where it is processed and excreted in the bile. As hyperlipidemic states increase in atherosclerosis the LDL cholesterol increases and HDL decreases. Effective hypolipidemic agents need to reverse this ratio since clinical data indicate that high HDL cholesterol and low LDL cholesterol protects man from myocardial infarctions. Thus, it is highly desirable to treat mammals afflicted with hyperlipidemia so as to lower VLDL and LDL fractions and increase the HDL fractions.

It is not surprising to find that a number of compounds have been proposed for the treatment o hyperlipidemia in mammals. Examples include U.S. Pat. No. 4,499,303 which describes the use of a novel class of N-benzoylsulfamates and benzoylsulfonamides as useful hypolipidemic agents. U.S. Pat. No. 4,395,417 proposes the use of cyclic imides, diones, reduced diones and analogs as useful agents. Orotic acid has been shown to decrease the plasma lipids blood level in rats.

U.S. Pat. No. 4,639,444 describes 3,5-dialkyl-4,6-diaryltetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as useful hypolipidemic agents. U.S. Pat. No. 4,681,893 teaches that certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and their ring opened acids are potent hypolipidemic agents. Likewise, U.S. Patent No. 4,351,844 describes hypocholesterolemic lactone compounds and their free acids which are derived from the natural fermentation product mevinolin. More recently, the control of hyperlipidemia through the use of a class of 4-pyrimidinecarboxylic acids has been described by Hall et al., J. Pharm. Sci, 74, 759 (1985).

In spite of the numerous compounds and methods which have been proposed for the control of hyperlipidemia, the need remains for drugs having enhanced lowering of elevated serum lipoprotein lipids.

Accordingly, it is the object of the present invention to provide a class of hypolipidemic compounds having enhanced capability in lowering LDL cholesterol and elevating HDL cholesterol. This and other objects of the present invention will be more apparent from the discussion which follows.

SUMMARY OF THE INVENTION

The present invention provides a method of controlling hyperlipidemia in mammals which comprises administering to a mammal an amount effective to control hyperlipidemia of a compound having hypolipidemic activity and the structural formula: ##STR3## wherein R¹ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, phenalkyl, cyano, --CO--R⁹ or --Y--CO--R⁹ ;

R² is ##STR4## R³ and R⁴ can be the same or different and are each the same as R¹ ;

R⁵, R⁶ and R⁷ can be the same or different and are each hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₁ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹,

with the proviso that R⁵ and R⁶ together cannot be so bulky as to cause the compound to decompose;

R⁸ is hydrogen, a C₁ to C₅ alkyl, a C₄ to C₁₀ cycloalkyl, --CO--R⁹, or --Y--CO--R⁹ ;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl;

R¹² is --CO, --COH, --CS, --CSH, or a C₁ to C₄ alkylene group; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene;

and the pharmaceutically acceptable salts, and mixtures thereof.

In addition, the present invention provides for pharmaceutical compositions for use in controlling hyperlipidemia in mammals which comprises a hypolipidemically effective amount of a compound having hypolipidemic activity and a structural formula (I) or a pharmaceutically acceptable salt thereof a shown above in combination with a pharmaceutically acceptable carrier.

As referred to herein, "hypolipidemic activity" is intended to refer to the ability of the compounds of formula (I) to lower levels of serum cholesterol and/or triglycerides in mammals to which the compound is administered.

Many of the above-described compounds which may be used as hypolipidemic agents are new, and hence, as a further embodiment of the present invention there is provided a novel class of compounds having hypolipidemic activity and the structural formula: ##STR5## wherein R¹ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, phenalkyl, cyano, --CO--R⁹ or --Y--CO--R⁹ ;

R³ and R⁴ may be the same or different and are each the same as R¹ ;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene; provided that R³ and R⁴ are not both hydrogen and further provided that neither R³ nor R⁴ is hydrogen when R¹ is phenyl.

A second class of novel hypolipidemic agents according to this invention have the structural formula: ##STR6## wherein R¹ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;

R⁵ and R⁶ can be the same or different and are each hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹,

with the proviso that R⁵ and R⁶ together cannot be so bulky as to cause the compound to decompose;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene; and the pharmaceutically acceptable salts thereof, and mixtures thereof;

provided that R¹ is not phenyl or chlorophenyl when R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is ethoxy or when R⁶ is hydrogen, R⁵ is --CO--R⁹, and R⁹ is ethoxy; and further provided that R¹ is not phenyl when R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is methoxy or when R⁶ is hydrogen, R⁵ is --CO--R⁹, and R⁹ is methoxy.

A third class of novel hypolipidemic agents according to this invention have the structural formula: ##STR7## wherein R¹ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;

R⁷ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹,

R⁸ is hydrogen, a C₁ to C₅ alkyl, a C₄ to C₁₀ cycloalkyl, --CO--R⁹, or --Y--CO--R⁹ ;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl;

R¹² is --CO, --COH, --CS, --CSH, or a C₁ to C₄ alkylene group; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene;

with the proviso that when R⁸ is hydrogen and R⁷ is ethoxy, R¹ is not phenyl, chlorophenyl, methoxyphenyl, or n-butyl.

Pharmaceutically acceptable salts and mixtures of the above-described compounds are expected to have similar activity.

DETAILED DESCRIPTION OF THE INVENTION

We have found that the above-described compounds of formulas (I) through (IV) effectively lower serum lipids in mammals. The term mammals as used herein is intended in its normal sense, and hence is inclusive of not only mice, rats, dogs, cats, horses, pigs, sheep, cows and other animals, but humans as well. Through the use of the hypolipidemic agents of the present invention, we observed the inhibition of activity of the rate limiting enzyme of cholesterol synthesis (HMG CoA reductase) as well as the lowering of the acyl CoA cholesterol acyl transferase (cholesterol ester), acetyl CoA carboxylase (fatty acid), sn glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase (triglyceride) and heparin induced lipoprotein lipase (release of triglycerides for apoproteins).

The hypolipidemic agents of the present invention afford reduction in both serum cholesterol and triglycerides and can be used in lower dosage amounts than commercially available agents such as nicotinic acid derivatives, clofibrate, cholestyramine and cholestipol. Through the use of the agents of the present invention we have observed significant increases in HDL-cholesterol and reduced levels of LDL cholesterol with an acceleration of lipid excretion via the feces with clearance of lipids from the blood compartment and tissues, e.g. the aorta wall.

As used herein, the terms "alkyl", "alkenyl", "cycloalkenyl", "cycloalkyl" and "alkoxy" refer to carbon containing substituents that may be straight chain or branched. The terms "substituted alkyl", "substituted alkenyl", "substituted alknyl", "substituted cycloalkyl", "substituted cycloalkenyl" and "substituted alcoxy" include those substituted with at least one common functional substituent selected from but not limited to the group consisting of alkoxy, oxo, alkoxy carbonyl, halogen, nitro, aryl, carbamoyl, amino, amido, acyloxy, hydroxy, carboxy, alkylhio, sulfoxide, sulfone, thiol, sulfonyl, sulfano, phosphono and silyl. Thus, examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and n-pentyl. Examples of alkoxy groups include methoxy and ethoxy. Exemplary of suitable cycloalkyl groups are cyclobutyl, cyclopentyl or cyclohexyl.

The terms "substituted phenyl" and "substituted phenoxy" refer to the presence on the aromatic ring of at least one common functional substituent selected from but not limited to the group of C₁ to C₅ alkyl, substituted C₁ to C₅ alkyl, C₁ to C₅ alkoxy, benzoyl, alkanoyl, alkoxy carbonyl, halogen, nitro, carbamoyl, amino, amido, acyloxy, hydroxy, carboxy, alkylthio, sulfoxide, sulfone, thiol, sulfonyl, sulfano, phosphono and silyl.

Halogen groups may be selected from bromine, chlorine, fluorine and iodine, and preferably from chlorine and bromine.

Our invention provides a method for treating hypolipidemia in mammals by administering a hypolipidemically effective amount of a compound of formula (I). Examples of compounds of formula (I) wherein R² is (a) are those wherein R¹ is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R³ and R⁴ may be the same or different and are each selected from the group consisting of hydrogen, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, and N-phenylcarbamoyl. Specific compounds of formula (I) wherein R² is (a) include 4-phenyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1-N-phenylcarbamoyl-1,2,4-triazolidine-3,5-dione, 4-phenyl- 1-ethoxycarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione, 4-methyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-phenylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4 -methoxyphenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, and 4-n-butyl-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-phenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)- 1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, and pharmaceutically acceptable salts and mixtures thereof.

Compounds of formula (I) wherein R² is (b) include those wherein R¹ is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R⁵ and R⁶ are the same or different and are each selected from the group consisting of hydrogen, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, phenoxycarbonyl, carbamoyl and substituted carbamoyl. It is appreciated that, if R⁵ and R⁶ are too bulky, such as in the case when both are aromatic, the compound wherein R² is (b) may decompose. Thus those compounds are intended to be excluded from the invention.

Exemplary of compounds of formula (I) wherein R² is (b) are 3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione, 3-phenyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione, 3-(4-methoxyphenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione, 4-n-butyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione, 3-phenyl-6-methoxycarbonyl-1,3,5-triazabicyclo[ 3.1.0]hexane-2,4-dione and pharmaceutically acceptable salts and mixtures thereof.

Compounds of formula (I) wherein R² is (c) include those wherein R¹ is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; R⁷ is an alkoxy having from 1 to 5 carbon atoms or phenoxy; and R⁸ is hydrogen or a C₁ to C₅ alkyl; and R¹² is --CO. Exemplary of the compounds of formula (I) wherein R² is (c) are 3-phenyl-6-ethoxycarbonyl-1,3,5-triazine-2,4(1H,3H)-dione; 3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-triazine-2,4(1H,3H)-dione; and pharmaceutically acceptable salts and mixtures thereof.

According to a further aspect, our invention provides novel compounds of formula (II) as defined above with the proviso that provided that both R³ and R⁴ are not hydrogen and that R¹ is not phenyl when either R³ and R⁴ is hydrogen and further provided that R⁹ is not --NHC₆ H₅ when R¹ is phenyl. Our invention further provides novel compounds of formula (III) as defined above provided that R¹ is not phenyl or chlorophenyl when R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is ethoxy or when R⁶ is hydrogen, R⁵ is --CO--R⁹, and R⁹ is ethoxy; and further provided that R¹ is not phenyl when R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is methoxy or when R⁶ is hydrogen, R⁵ is --CO--R⁹, and R⁹ is methoxy. Novel compounds of formula (IV) as defined above are also provided with the proviso that when R⁸ is hydrogen and R⁷ is ethoxy, R¹ is not phenyl, chlorophenyl, methoxyphenyl, or n-butyl.

Included compounds from within the class defined by formula (II) are those wherein R¹ is selected from the group consisting of halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, and nitrophenyl; and R³ and R⁴ are each selected from the group consisting of hydrogen, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, and a carbamoyl or substituted carbamoyl with the proviso that both R³ and R⁴ are not both hydrogen.

Exemplary of novel hypolipidemic compounds of formula (II) are 4-phenyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-b 1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, and 4 -n-butyl-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione 4-(4-chlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-n butyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-phenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione, and pharmaceutically acceptable salts and mixtures thereof.

Novel compounds from within the class defined by formula (III) include those wherein R¹ is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R⁵ and R⁶ may be the same or different and are each selected from the group consisting of hydrogen and alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms.

Exemplary of novel hypolipidemic compounds of formula (III) are 3-(4-methoxyphenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione, 3-n-butyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione, 3-(4-nitrophenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione and pharmaceutically acceptable salts and mixtures thereof.

Compounds from within the class defined by formula (IV) include those wherein R¹ is selected from the group consisting of halophenyl, nitrophenyl and alkoxyphenyl wherein the alkoxy group contains from 1 to 5 carbon atoms but is not ethoxy when R¹ is chlorophenyl.

As noted, the pharmaceutically acceptable salts of the compounds of formulas (I) through (IV) can be used. These salts may be acid addition salts formed from inorganic or organic, e.g. hydrochlorides, sulfates, phosphates, benzoates or acetates, or salts formed with bases, e.g. alkali metal salts such as sodium or potassium salts.

The amount of hypolipidemically active compound as defined by formulas (I) through (IV) (including esters and pharmaceutically acceptable salt thereof) which is required for the treatment of patients suffering from elevated lipid levels will vary with the route of administration, the condition of the patient under treatment and is ultimately at the discretion of the attending physician. However, a suitable dose of the active compound is in the range of from about 1 to about 100 mg/kg body weight per day; preferably from about 4 to about 16 mg/kg daily. Thus, for example, when administered to man (of approximately 70 kg body weight) in multiple daily doses, a typical unit or subdose of the active compound is about 150 mg.

The form of the dose is not critical and may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or inefflation. Oral administration is preferred

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croacarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. Suitably, a 1% aqueous solution of carboxymethylcellulose may be employed.

The compounds of formulas (I) through (IV) or their salts may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formulas (I) through (IV) and their physiologically acceptable acid addition r basic salts may be formulated for parenteral administration by injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose forms with an added preservative.

The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

It will therefore be appreciated that the compounds of formulas (I) through (IV) o their pharmaceutically acceptable salts, may be used in the manufacture of a medicament for the treatment of human or animal subjects suffering from hyperlipidemia.

EXPERIMENTAL

Melting points and boiling points are uncorrected. Infrared spectra were recorded on a Beckman Acculab 10 spectrophotometer. Ultraviolet spectra were obtained on a Beckman DBG spectrophotometer. ¹ H NMR spectra were recorded on a Varian EM-360A spectrometer. Mass spectra were determined on an AEI-902 mass spectrometer at the Research Triangle Institute of Mass Spectrometry, Research Triangle Park, N.C. Elemental analyses were performed by Integral Microanalytical Laboratories, Raleigh, N.C. and Desert Analytics, Phoenix, Ariz.

Generally, derivatives of 1,2,4-triazolidine-3,5-diones (Compounds of formula (I)(a) and (II)) ma be synthesized by reacting 4-substitute 1,2,4-triazolidine-3,5-diones synthesized by the stepwise procedure of Cookson, Gupte, Stevens, and Watts, Org. Syn. 1871, 51, 121, with carboxylic acid anhydrides or alkoxy chloroformates wherein the alkoxy group has from 1 to 5 carbon atoms in the presence of sodium hydride, or aryl isocyanates in the presence of sodium hydride. 1- and 1,2-alkyl substituted derivatives can be made by reacting 4-substituted 1,2,4-triazolidine-3,5-diones with alkyl halides or cycloalkyl halides in the presence of a base, e.g. KOH. This latter method can also be used to prepare alkenyl, cycloalkenyl and alkynyl derivatives so long as the multiply bonded group is not directly attached to the ring nitrogen. To attach a phenyl in the R³ or R⁴ position, phenylhydrazine should be used to cyclize the triazolidine-3,5-dione ring.

Derivatives of 1,3,5-triazine-2,4-(1H,3H)-diones (Compounds of formula (I)(c) and (IV) may be synthesized by heating a solution of a compound of formula (I)(b) or (III) in chlorobenzene at reflux for weeks.

The following specific examples illustrate the preparation of compounds defined by formulas (I) through (IV) and are according to the invention, but are not to b construed as limiting the scope thereof.

PREPARATION OF COMPOUNDS OF FORMULA (I)(a) AND (II)

The 4-substituted 1,2,4-triazolidine-3,5-diones were prepared by the stepwise procedure of Cookson, Gupte, Stevens and Watts, Org. Synth. 1971, 51, 121.

General Procedure for the Synthesis of the 1-Alkylcarbonyl-4-substituted-1,2,4-triazolidine-3,5-diones

To a stirred suspension of the 4-substituted 1,2,4-triazolidine-3,5-dione (30 mmol) in 150 to 200 ml of chloroform at room temperature was added dropwise the carboxylic acid anhydride or other appropriate acylating agent (450 mmol). The reaction mixture was stirred at room temperature or heated under reflux, as required, for one to five days. The reaction mixture was filtered to remove the 1-acylated 4-substituted 1,2,4-triazolidine-3,5-dione and unreacted 1,2,4-triazolidiine-3,5-dione. This solid mixture was not always present depending on the anhydride used in the reaction. Treatment of the filtered solid with water removed the unreacted 1,2,4-triazolidine-3,5-dione to give the 1-alkylcarbonyl-1,2,4-triazolidine-3,5-dione, which was purified by recrystallization from ethanol:water. The filtrate was washed with three 100 ml portions of water and three 80 ml portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid to precipitate an additional quantity of the 1-alkylcarbonyl-4-substituted-1,2,4-triazolidine-3,5-dione.

Preparation of 1-Methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione

To a suspension of 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride with stirring. The reaction mixture was stirred at room temperature for five days. The reaction mixture was filtered to remove a white precipitate which was washed with 30 ml of chloroform to give 3.55 g (54.0 %) of 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione as white solid, m.p. 215°-218.5° C. The filtrate Was washed with three 100 ml portions of water and three 80 ml portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was formed. The chloroform solution was dried (Na₂ SO₄) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride. The filtered solid was recrystallized from 95% ethanol to yield pure 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: m.p. 216.5° -218.5° C.; IR (Nujol) 1726, 1710, 1688 cm-¹ (CO); ¹ H NMR (60 MHz, CDCl₃) δ 7.90 (s, 5H) 2.55(s, 3H). Found: C, 54.5; H, 4.2: N, 19.4. C₁₀ H₉ N₃ O₃ requires C, 54.8; H, 4.2; N, 19.4.

Preparation of 1-Methylcarbonyl-4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione

To a suspension of 6.38 g (30 mmol) of 4-(4-chlorophenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride with stirring. The reaction mixture was stirred at room temperature for five days. The reaction mixture was filtered. The filtrate was washed with three 100 ml portions of water and three 80 ml portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid to yield a precipitate of the triazolidine-3,5-dione product. In some instances a precipitate, which was presumably the sodium salt of the triazolidine-3,5-dione, formed in the sodium carbonate washings prior to acidification. In these instances the precipitate was filtered from the carbonate washings and dissolved in hot water prior to acidification. The chloroform solution was dried (Na₂ SO₄) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride. The filtered triazolidine-3,5-dione was recrystallized from 95% ethanol to yield pure 1-methylcarbonyl-4 -(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione as a white solid: m.p. 201°-203° C.; IR (Nujol) 1729, 1710, and 1690 cm⁻¹ (CO); ¹ H NMR (60 MHz, CDCl₃ δ 7.5(m, 4 H), 2.5 (s, 3 H). Found: C,47.31; H, 3.10; N, 16.63; M⁺ (70 eV) 253.0253. C₁₀ H₈ N₃ O₃ Cl requires C, 47.35; H, 3.18; N, 16.57; M⁺ 253.0254.

General Procedure for the Synthesis of the 1,2-Dialkylcarbonyl-4-substituted-1,2,5-triazolidine-3,5-diones

To a stirred mixture of the 4-substituted 1,2,4-triazolidine-3,5-dione (30 mmol) and lead diacetate trihydrate (60 mmol) in 200 ml of chloroform was added dropwise the carboxylic acid anhydride or appropriate acylating agent (450 mmol). The reaction mixture was stirred at room temperature until all the solids had dissolved. The solution was washed with three 100 ml portions of water and three 100 ml portions of 10% sodium carbonate. Acidification of the carbonate washings with concentrated hydrochloric acid did not produce a precipitate. The chloroform solution was dried (Na₂ SO₄) and evaporated under reduced pressure to give a solid-liquid mixture. The mixture was filtered and the solid was recrystallized from alcohol:water to yield the pure 1,2-dialkylcarbonyl-4-substituted-1,2,4-triazolidine-3,5-dione. Acetate salts such as sodium acetate can be used in place of lead diacetate trihydrate in the reaction mixture.

Preparation of 1,2-Dimethylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione

To a mixture of 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione and 22.7 g (60 mmol) of lead diacetate trihydrate in 200 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride. The mixture was stirred at room temperature. After 25 hours the pale yellow solution was washed with three 100 ml portions of water and three 75 ml portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was produced. The chloroform solution was dried (Na₂ SO₄) and evaporated under reduced pressure to give a solid-liquid residue. The residue was filtered and the filtered solid was washed with 25 ml of 95% ethanol to give 2.75 g (35.1%) of the 1,2,4-triazolidine-3,5-dione product as a white solid. An additional quantity of the product precipitated from the ethanol filtrate. This solid was filtered to give an additional 1.20 g (15.3%) of the 1,2,4-triazolidine-3,5-dione product (50.4% total yield). The solids were recrystallized from 95% ethanol to give pure 1,2-dimethylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: m.p. 169°-170.5° C.; IR (Nujol) 1750, 1732 (shoulder), 1714 (shoulder) Cm⁻¹ (CO); ¹ H NMR (60 MHz, CDCl₃) δ 7.80(s, 5H), 2.55 (s, 6H); Found: C, 55.2; H, 4.45; N, 16.0; C₁₂ H.sub. 11 N₃ O₄ requires C, 55.2; H, 4.2; N, 16.0.

Preparation of 1,2-Dimethylcarbonyl-4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione

To a mixture of 1.00 g (4.83 mmol) of 4-methoxyphenyl-1,2,4-triazolidine-3,5-dione and 3.80 g (10 mmol) of lead diacetate trihydrate in 40 ml of chloroform was added dropwise over a 10 minute period 7.70 g (75 mmol) of acetic anhydride. The solution was stirred at room temperature for five hours. The clear solution was washed three times with 20 ml portions of water and three times with 15 ml portions of 10% sodium carbonate. The sodium carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was obtained. The chloroform solution was dried (Na₂ SO₄) and evaporated to dryness under reduced pressure to give a solid-liquid residue. The residue was washed with five ml of 95% ethanol and recrystallized from methanol to give pure 1,2-dimethylcarbonyl-4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione: m.p. 148°-150° C.; IR (Nujol) 1710, 1750 cm³¹ 1 (CO); ¹ H NMR (300 MHz, CDCl₃) δ 7.37-6.98 (m, 4H), 3.84 (s, 3H), 2.65(s, 6H); Found: C, 53.4; H, 4.4; N, 14.4. C₁₃ H₁₃ N₃ O₅ requires C, 53.6; H, 4.5; N, 14.4.

Preparation of 1,2-di-n-Pentylcarbonyl-4-(4-methyoxphenyl)-1,2,4-triazolidine -3,5-dione

To a mixture of 1.00 g (4.83 mmol) of 4-methoxyphenyl-1,2,4-triazolidine-3,5-dione and 3.80 g (10 mmol) of lead diacetate trihydrate in 40 ml of chloroform was added dropwise over a 10 minute period 7.70 g (75 mmol) of hexanoic anhydride. The solution was stirred at room temperature for five hours. The clear solution was washed three times with 20 ml portions of water and three times with 15 ml portions of 10% sodium carbonate. The sodium carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was obtained. The chloroform solution was dried (Na₂ SO₄) and evaporated to dryness under reduced pressure to give a solid-liquid residue. The residue was washed with five ml of 95% ethanol and recrystallized from methanol to give pure 1,2-di-n-pentylcarbonyl-4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione: m.p. 88°-90° C.; IR (Nujol) 1742, 1710 cm⁻¹ (CO); ¹ H NMR (300 MHz, CDCl₃) δ 7.36-6.97 (m, 4H), 3.83 (s, 3H), 2.97 (t, 4H), 1.76 (m, 4H), 1.35 (m, 8H), 0.89 (distorted t, 6H); Found: C, 62.3; H, 7.0; N, 10.3. C₂₁ H₂₉ N₃ O₅ requires C, 62.5; H, 7.3; N, 10.4.

Preparation of 1,2-Diethylcarbonyl-b 4(4-nitrophenyl)-1,2,4-triazolidine-3.5-dione

To a mixture of 1.00 g (4.50 mmol) of 4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione and 3.80 g (10 mmol) of lead diacetate trihydrate in 40 ml of chloroform was added dropwise over a 10 minute period 9.80 g (75 mmol) of propanoic anhydride. The solution was stirred at room temperature for five hours. The clear solution was washed three times with 20 ml portions of water and three times with 15 ml portions of 10% sodium carbonate. The sodium carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was obtained. The chloroform solution was dried (Na₂ SO₄) and evaporated to dryness under reduced pressure to give a solid-liquid residue. The residue was washed with five ml of 95% ethanol and recrystallized from methanol to give 1,2-diethylcarbonyl-4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione: m.p. 140°-142° C.; IR (Nujol) 1750, 1705 cm⁻¹ (CO); ¹ H NMR (300 MHz, CDCl₃) δ 8.4-7.24 (m, 4H), 3.03 (q, 4H), 1.28 (t, 6H); Found: C, 49.9; H, 4.0; N, 16.7. C₁₄ H₁₄ N₄ O₆ requires C, 50.2; H, 4.2; N, 16.8.

Preparation of 1,2-Di-n-pentylcarbonyl-4-n-butyl-1,2,4-triazolidine-3,5-dione

To a mixture of 1.00 g (6.37 mmol) of 4-n-butyl-1,2,4-triazolidine-3,5-dione and 4.60 g (12 mmol) of lead diacetate trihydrate in 40 ml of chloroform was added dropwise over a 10 minute period 19.5 g (91 mmol) of hexanoic anhydride. The solution was stirred at room temperature for five hours. The clear solution was washed three times with 20 ml portions of water and three times with 15 ml portions of 10% sodium carbonate. The sodium carbonate washing were acidified with concentrated hydrochloric acid. No precipitate was obtained. The chloroform solution was dried (Na₂ SO₄) and evaporated to dryness under reduced pressure to give a solid-liquid residue. The residue was washed with five ml of 95% ethanol and recrystallized from methanol to give pure 1,2-di-n-pentycarbonyl-4-n-butyl-1,2,4-triazolidine-3,5-dione: m.p. 88°-89° C.; IR (Nujol) 1736, 1715 cm⁻¹ (CO); ¹ H NMR (300 MHz, CDCl₃) δ 2.91 (t, 4H), 1.77-1.29 (m, 18H), 0.89 (m, 9H); Found: C, 60.95; H, 8.9; N, 11.85. C₁₆ H₃₁ N₃ O₄ requires C, 61.15; H, 8.9; N, 11.9.

PREPARATION OF COMPOUNDS OF FORMULA (I)(b) AND (III)

Methyl diazoacetate was synthesized by the procedure of Searle, U.S. Pat. No. 2,490,714 (1949) and Chem. Abstr. 1950, 44, 3519. The 4-substituted 3-H-1,2,4-triazoline-3,5-diones were prepared by the stepwise procedure of Cookson, Gupte, Stevens, and Watts, Org. Synth., 1971, 51, 121. t-butyl hypochlorite was prepared using the method of Teeter and Bell, Org. Synth. Coll., Vol. IV, 1963, 125. Ethyl diazoacetate was purchased commercially.

Reactions of diazoalkanes with 3-H-1,2,4-triazoline-3,5(4H)-diones have been previously described. See Izydore, R. A., McLean, S., J. Am. Chem. Soc. 1975, 97. 5611.

General Procedure for the Synthesis of the 6-Alkyoxycarbonyl-3-substitute-1,3,5-triazalcyclo[3.1.0]Hexane-2,4-diones

To a solution of the 3-H-1,2,4-triazoline-3,5(4H)-dione (20 mmol) in dichloromethane (200 ml) at 0° C. was added dropwise over 10 minutes the diazoalkane, with stirring. Stirring was continued until the red color of the triazolinedione had faded. The solution was then filtered and evaporated to dryness under reduced pressure. The resulting solid was purified by recrystallization by first dissolving it in hot carbon tetrachloride-chloroform (1:1), and then cooling the solution to room temperature, and finally by adding petroleum ether (b.p. 40°-60° C.) or hexane dropwise with swirling to precipitate a compound of formula (I)(b) and (III).

Preparation of 6-Ethoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione

To a solution of 1.5 g (8.5 mmol) of 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml of dichloromethane at 0° C. was added dropwise over 10-20 minutes 0.97 g (8.5 mmol) of ethyl diazoacetate, with stirring. Gas evolution was noted. The deep red solution was allowed to warm to room temperature, and stirring was continued overnight. The resulting amber solution was evaporated to dryness under reduced pressure to yield 2.17 g (98%) of the crude bicyclic product. The product was purified by heating it in 20 ml of hot carbon tetrachloride, adding chloroform dropwise until the solid had dissolved, cooling the solution to room temperature, and adding petroleum ether (40°-60° C.) dropwise with swirling to precipitate pure 6-ethoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione: m.p. 175°-177° C. (decomp.); IR (Nujol) 1745 cm⁻¹ (CO); ¹ H NMR (400 MHz, CDCl₃) δ 1.3 (3H, br m, CH₃), 3.8 (1H, br s, CH), 4.3 (2H, br m, OCH₂), and 7.5 (5H, m, Ph); ¹³ C NMR (100.5 MHz; CDCl₃ ; ¹ H decoupled) 13.0-14.5 (overlapping s, CH₃), 62.0-65.5 (overlapping s, OCH₂ and CH), 124.5-27.5 and 128.0-131.5 (overlapping s, Ph), and 152.8-165.0 (br overlapping s, CO). Found: C, 55.3; H, 4.1; N, 16.0; M⁺ (70 eV), 261. C₁₂ H₁₁ N₃ O₄ requires C, 55.2; H, 4.25; N, 16.1; M⁺, 261.

Preparation of 6-Methoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione

To a solution of 2.05 g (11.7 mmol) of 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml of dry ethyl acetate at 0° C. under nitrogen was added dropwise over a 20 minute period 1.10 g (11 mmol) of methyl diazoacetate with stirring. The deep red solution was kept at 0° C. for one hour and warmed to room temperature. Stirring was continued overnight. The pale yellow solution was filtered and evaporated to dryness under reduced pressure to give a light yellow solid. The solid was purified by heating it in 10 ml of hot carbon tetrachloride, adding chloroform (approximately 10 ml) to the mixture dropwise until the solid dissolved, cooling the solution to room temperature, and adding petroleum ether (b.p. 40°-60° C.) dropwise with vigorous mixing. The precipitated solid was filtered and dried to yield 2.50 g (92%) of pure 6-methoxycarbonyl-3-phenyl-1,3,5-triazabicyclo [3.1.0]hexane-2,4-dione as a white solid: M.P. 176°-177° C. (decomp.). IR (Nujol) 1740 cm⁻¹ (CO); ¹ H NMR (100 MHz; CDCl₃ 3.75 (1H, br s, CH), 3.88 (3 H, br m, OMe), and 7.45 (5H, m, Ph); ¹³ C NMR (25.2 MHz; CDCl₃ ; ¹ H decoupled) δ 54.0 (br, OMe and CH), and 123-126 and 128-131 (br, overlapping s, Ph): Found: C, 53.1: H, 3.8; N, 16.85: M³⁰ (70 eV), 247. C₁₁ H₉ N₃ O₄ requires C, 53.4; H, 3.6; N, 17.0; M⁺, 247.

Preparation of 6-Ethoxycarbonyl-3-(4-chlorophenyl)-1,3.5-triazabicyclo[3.1.0]-hexane-2,4-dione

To a solution of 2.33 g (11 mmol) of 4-(4-chlorophenyl)-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml of dichloromethane at 0° C. under nitrogen was added dropwise over a 20 minute period 1.25 g (11 mmol) of ethyl diazoacetate. The deep red solution was kept at 0° C for one hour and allowed to warm to room temperature. Stirring was continued overnight. The pale yellow solution was filtered and evaporated to dryness under reduced pressure to give 3.08 g (95%) of the crude bicyclic product as a light yellow solid. The solid was purified by heating it in 30 ml of hot carbon tetrachloride, adding chloroform (approximately 25 ml) dropwise until the solid dissolved, cooling the solution to room temperature, and adding petroleum ether (b.p. 40°-60° C.) dropwise with mixing. The precipitated solid was filtered and dried to yield pure 6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione as a white solid: M.p. 174°-76° C. (decomp.). IR (Nujol) 1740 cm⁻¹ (CO); ¹ H NMR (100 MHz; CDCl₃) δ 1.3 (3H, br m, CH₃), 4.25(1H, br m, CH), 4.35(2H br m, OCH₂, and 7.5 (4H, m, 4-CDClH₄) ¹³ C NMR (100.5 MHz; CDCl₃ ; ¹ H decoupled) 13.0-14.5 (overlapping CH₃), 62.0-65.5 (overlappings, CH and OCH₂), and 133.2-137.5 (overlappings, 4-ClC₆ H₄), and 148.0-166.0 (br overlappings, CO). Found: C, 48.6; H, 3.4; N, 14.0; M⁺ (70 eV), 295.0362. C₁₂ H₁₀ N₃ O₄ requires C, 48.75; H, 3.4; N, 14.2; M+, 295.0360.

Preparation of 6-Ethoxycarbonyl-3-(4-methoxyphenyl)-1,3,5-triazabicyclo[3.1.0]-hexane-2,4-dione

To a solution of 2.28 g (11 mmol) of 4-(4-methoxyphenyl)-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml of dichloromethane at 0° C. under nitrogen was added dropwise over a 20 minute period 1.25 g (11 mmol) of ethyl diazoacetate. The deep red solution was kept at 0° C. for one hour and allowed to warm to room temperature. Stirring was continued overnight. The pale yellow solution was filtered and evaporated to dryness under reduced pressure to give 2.89 g (90%) of the crude bicyclic product as a light yellow solid. The solid was purified by heating it in 10 ml of hot carbon tetrachloride, adding chloroform (approximately 10 ml) dropwise until the solid dissolved, cooling the solution to room temperature, and adding cyclohexane dropwise with mixing. The precipitated solid was allowed to sit for two hours, filtered, washed with five ml of carbon tetrachloride, and dried to yield pure 6-ethoxycarbonyl-3-(4-methoxyphenyl)-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione as a white solid: m.p. 175°-178° C. (decomp.). IR (Nujol) 1740 cm⁻¹ (CO); ¹ H NMR (60 MHz; CDCl₃) δ 1.3 (3H, br m, CH₂ CH₃), 3.7 (3H, br m, OMe), 4.3 (3H, br m, CH and OCH₂), and 6.4-7.6 (4H, m, 4-MeO-C₆ H₄). Found: C, 53.65; H, 4.7; N, 14.4. C₁₃ H₁₃ N₃ O₅ requires C, 53.6; H, 4.5; N, 14.4.

Preparation of 6-Ethoxycarbonyl-3-n-butyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione

To a solution of 1.73 g (11 mmol) of 3-n-butyl-3H-1,2,4-triazoline-3,5-(4H)-dione in 100 ml of dichloromethane at 0° C. under nitrogen was added dropwise over a 20 minute period 1.25 g (11 mmol) of ethyl diazoacetate. The deep red solution was kept at 0° C. for one hour and allowed to warm to room temperature. Stirring was continued overnight. The pale yellow solution was filtered and evaporated to dryness under reduced pressure to give 2.38 g (90%) of the crude bicyclic product as a light yellow solid. The solid was purified by dissolving it in 20 ml of carbon tetrachloride an adding cyclohexane dropwise with mixing to effect precipitation. The precipitated solid was filtered and dried to yield pure 6-ethoxycarbonyl-3-n-butyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione as a white solid: m.p. 94°-96° C. (decomp.); IR (Nujol) 1740 cm⁻¹ (CO); ¹ H NMR (60 MHz; CDCl.sub. 3) δ 0.6-1.9 (10 H, br m, CH₃ (CH₂)₂ and CH₃ CH₂ O), 3.5 (2H, br m, CH₂ N), and 4.2 (2H, br m, OCH₂). Found: C, 49.6; H, 6.4; N, 17.1 C₁₀ H₁₅ N₃ O₄ requires C, 49.8; H, 6.3; N, 17.4.

PREPARATION OF COMPOUNDS OF FORMULA (I) (C) AND (IV) General Procedure for the Synthesis of the 6-alkoxycarbonyl-3-aryl-1,3,5-triazine-2,4(¹ H,3H)-diones

A solution of the bicyclic diaziridine (formula (I)(b) or (III)) (20 mmol) in chlorobenzene (250 ml) was heated at reflux for two weeks. The reaction mixture was cooled to room temperature, and the precipitate was removed by filtration. The filtered solid was stirred in methylene chloride (200 ml) for 30 min and filtered to remove the triazolo[1,2-a]triazole-1,3,5,7-tetraone (25-35%). The methylene chloride solution was evaporated to dryness under reduced pressure to give the crude triazine. Purification was accomplished by recrystallization from chloroform-cyclohexane or chloroform-petroleum ether (b.p. 40°-60° C.). If necessary the recrystallized product was further purified by preparative t.l.c. on silica gel. It was necessary to heat the purified product under vacuum to drive off the purification solvents.

Preparation of 6-Ethoxycarbonyl-3-phenyl-1,3,5-triazine-2,4(1H,3H)-dione

A solution of 7.0 g (26.8 mmol) of 6-ethoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione in 250 ml of chlorobenzene was heated to reflux for two weeks during which time a precipitate slowly formed. After cooling the reaction mixture to room temperature, the precipitate was filtered to yield 3.3 g of crude solid. The solid was stirred in 200 ml of dichloromethane for 30 minutes and filtered. The filtered solid was washed with an additional 50 ml of dichloromethane to give 1.5 g (35%) of 2,6-diphenyltriazolo[1,2a]triazole-1,3,5,7-tetraone: m.p. greater than 310° C. The combined methylene chloride washings were evaporated under reduced pressure to yield 1.5 g (21%) of crude 6-ethoxycarbonyl-3-phenyl-1,3,5-triazine-2,4(1H,3H)-dione: m.p. 158°-164° C. (decomposition). The 1,3,5-triazinedione product was purified as follows: A quantity weighing 1.00 g of the 1,3,5-triazinedione was heated in 20 ml of boiling carbon tetrachloride. To the hot mixture was added in 5 ml portions 20 ml of chloroform to dissolve the solid. The hot solution was filtered, and the filtrate was cooled to room temperature. The cool filtrate was added to 200 ml of cyclohexane at room temperature with mixing to precipitate 0.0 g of an off-white solid: m.p. 168°-170° C. In place of cyclohexane, petroleum ether (b.p. 40°-60° C.) may be substituted. It was generally observed that addition of cyclohexane to the carbon tetrachloride-chloroform filtrate led to the formation of a gummy precipitate. The off-white solid was heated at 110° C. in a heating pistol to drive off the remaining recrystallization solvents to yield pur 6-ethoxycarbonyl-3-phenyl-1,3,5-triazine-2,4(1H,3H)-dione as a white solid: M.p. 168°-170 C. (decomp.). IR (Nujol) 3440 (NH), 1746 (CO), 1779 (CO), and 1607 cm⁻¹ (C=N); UV_(max) (MeOH) 257 nm ( ε 3700); ¹ H NMR (60 MHz, acetone-d₆) δ 1.37 (3H, t, CH₃), 4.39 (2H, q, OCH₂), and 7.31 (5 H, m, ph). Found: C, 55.05; H, 4.2; N, 16.5; M⁺ (70 eV), 261.0747; C₁₂ H₁₁ N₃ O₄ requires C, 55.2; H, 4.3; N, 16.1; M⁺, 61.0749.

Preparation of 6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazine-2,4(1H,3H)-dione

A solution of 6.0 g (20.3 mmol) of 6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione in 250 ml of chlorobenzene was heated at reflux for two weeks during which time a precipitate slowly formed. After cooling the reaction mixture to room temperature, the precipitate was filtered to yield 2.13 g of crude solid. The solid was stirred in 200 ml of dichloromethane for 30 minutes and filtered. The filtered solid was washed with an additional 50 ml of dichloromethane to give 1.0 g (25%) of 2,6-di-(4-chlorophenyl)-triazolo[1,2-a]triazol-1,3,5,7-tetraone, m.p. greater than 310° C. The combined methylene chloride washings were evaporated under reduced pressure to yield 1.08 g (18.0%) of crude 6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazine-2,4(1H,3H)-dione: m.p. 191°-196° C. (decomposition). The 1,3,5-triazinedione product was recrystallized by heating 0.50 g of the product in 60 ml of boiling carbon tetrachloride, with stirring. A total of 55 ml of chloroform was then added in five ml portions to dissolve the solid. The hot solution was filtered, and then filtrate was cooled to room temperature. The cooled filtrate was added dropwise to 200 ml of cyclohexane with stirring to precipitate 0.21 g of an off-white solid: m.p. 203°-205° C. It was generally observed that addition of cyclohexane to the carbon tetrachloride-chloroform filtrate led to the formation of a gummy precipitate. In place of cyclohexane petroleum ether (b.p. 40°-60° C.) may be substituted. In an alternate procedure 0.80 g of the product was dissolved in 25 ml of cold acetone. The solution was filtered, and the filtrate was added slowly with swirling to precipitate 0.45 of an off-white solid: m.p. 191°-196° C. The recrystallized product was purified by preparative thin-layer chromatography (TLC) as follows: A sample of the recrystallized product weighing 0.35 g (1.2 mmol) was dissolved in 2.0 ml of HPLC grade ethyl acetate and applied in a thin streak 1.0 cm high across the bottom of 20 cm×20 cm silica TLC plates. Twelve plates were used. The plates were developed in a closed chamber using glacial acetic acid as the mobile phase. The plates were air-dried. Analysis under UV light (254 nm) revealed the presence of two components having R_(f) values of 1.00 and 0.90, respectively. Each of the separated components was scraped from the plates and combined. Each of the components was then extracted into 50 ml of dichloromethane, filtered, and the solvent removed under reduced pressure to give a solid residue. The solid corresponding to the slower moving component (R_(f) =0.90) weighed 0.15 g: m.p. 212°-215° C. This solid was recrystallized by dissolving it in 20 ml chloroform-carbon tetrachloride (50:50) and adding the resulting solution to 100 ml of cyclohexane. The precipitate was filtered to give 0.090 g of pure 6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazine-2,4(1H,3H)-dione as a white solid: M.P. 214-215 1/2C (decomp.). IR (Nujol) 3430 (NH), 1759 (CO), 1740 (CO), 1666 (CO), and 1590 cm⁻¹ (C=N); UV_(max) (MeOH) 260 nm (3900); ¹ H NMR (60 MHz, acetone-d₆) δ 1.39 (3H, t, CH₃), 4.38 (2H, q, OCH₂), 4.8 (1H, br s, NH), and 7.37 (4H, m, 4-ClC₆ H₄). Found: C, 48.65; H, 3.3; N, 14.0; M⁺ (70 eV), 295.0362; C₁₂ H₁₀ N₃ O₄ Cl requires C, 48.7; H, 3.4; N, 14.2; M⁺, 295.0360.

Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts of the compounds of general formulas (I) through (IV), using conventional methods.

TESTING OF NORMAL MICE

The following compounds were tested for their hypolpidemic activity in CF₁ mice.

    ______________________________________                                         Compound No.                                                                             Name                                                                 ______________________________________                                         Parent    1,2,4-triazolidine-3,5-dione                                         A         4-phenyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-                              dione                                                                B         4-phenyl-1,2-dimethylcarbonyl-1,2,4-triazolidine-                              3,5-dione                                                            C         4-phenyl-1-ethoxycarbonyl-1,2,4-triazolidine-3,5-                              dione                                                                D         4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-                                     triazolidine-3,5-dione                                               E         4-phenyl-1,2,4-triazolidine-3,5-dione                                F         4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione                     G         4-(4-n-butyl)-1,2,4-triazolidine-3,5-dione                           H         4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione                       I         4-phenyl-1-N--phenylcarbamoyl-1,2,4-triazolidine-                              3,5-dione                                                            J         4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione                      K         4-methyl-1,2,4-triazolidine-3,5-dione                                L         3-(4-chlorophenyl)-6-ethoxyacarbonyl-1,3,5-                                    triazabicyclo[3.1.0]hexane-2,4-dione                                 M         3-phenyl-6-ethoxycarbonyl-1,3,5-                                               triazabicyclo[3.1.0]hexane-2,4-dione                                 N         3-phenyl-6-ethoxycarbonyl-1,3,5-triazine-                                      2,4(1 --H,3 --H)-dione                                               O         3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-                                     triazine-2,4(1 --H,3 --H)-dione                                      P         4(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4-                                 triazolidine-3,5-dione                                               Q         4.(4-methoxyphenyl)-1,2-diphenylcarbonyl-1,2,4-                                triazolidine-3,5-dione                                               R         4.(4-methoxyphenyl)-1,2 diethylcarbonyl-1,2,4-                                 triazolidine-3,5-dione                                               S         4-(4-nitrophenyl)-1,2 diethylcarbonyl -1,2,4-                                  triazolidine-3,5-dione                                               T         4-(4- -n-butyl)-1,2 dipentylcarbonyl-1,2,4-                                    triazolidine-3,5-dione                                               U         4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-                                 triazolidine-3,5-dione                                               V         4-(4-chlorophenyl)1-pentylcarbonyl (2 --H)-1,2,4-                              triazolidine-3,5 dione                                               ______________________________________                                    

Compounds A-V as defined above, were suspended in an aqueous 1 percent carboxymethylcellulose (CMC) solution and homogenized. Each of the so prepared compounds were administered to a group of six CF₁ male mice, each weighing approximately 25 grams, intraperitioneally for 16 days. Each of these compounds were provided in a dosage of 20 mg/kg/d ip. On Days 9 and 16 blood was obtained by tail vein bleeding. The blood serum so obtained was separated by centrifugation for three minutes. Serum cholesterol levels were determined by a modification of the Liebermann-Burchard reaction (Ness, Clin. Chim. Acta., Vol. 10, 229 [1964]). Serum triglyceride levels were determined on Day 16 by use of the Fisher, Hycel Triglyceride Test Kit.

In addition to the above-described treated mice, an untreated control group of six mice were similarly tested on Days 9 and 16 to determine their serum cholesterol and trigylceride blood levels. Based on the results obtained for the untreated control group, the percent control, based on serum cholesterol and serum triglyceride levels of the treated mice compared to the untreated mice, was obtained. Table 1 reports this percent control, including standard deviation, indicating the level of confidence of these numbers.

    ______________________________________                                                   Serum Cholesterol*                                                                          Serum Triglyceride                                      Compound No.                                                                               Day 9     Day 16   Day 16                                          ______________________________________                                         Parent      81        79       73                                              A           67 ± 5 61 ± 6                                                                               48 ± 6                                       B           70 ± 6 64 ± 5                                                                               61 ± 5                                       C           73 ± 7 69 ± 5                                                                               62 ± 6                                       D           73 ± 4 64 ± 6                                                                               55 ± 7                                       E           71 ± 5 48 ± 3                                                                               68 ± 6                                       F           75 ± 5 56 ± 4                                                                               58 ± 3                                       G           71 ± 6 69 ± 5                                                                               79 ± 8                                       H           73 ± 5 66 ± 5                                                                               47 ± 5                                       I           79 ± 7 74 ± 6                                                                               68 ± 6                                       J           90 ± 5 58 ± 4                                                                               43 ± 4                                       K           88 ± 6 67 ± 5                                                                               89 ± 5                                       L           74 ± 3 56 ± 5                                                                               66 ± 7                                       M           62 ± 6 57 ± 5                                                                               59 ±  6                                      N           63 ± 6 54 ± 5                                                                               51 ± 2                                       O           63 ± 4 57 ± 4                                                                               55 ± 6                                       P           76        57       49                                              Q           67        86       75                                              R           62        63       62                                              S           72        36       62                                              T           69        49       53                                              U           72        51       51                                              V           77        52       42                                              1% Carboxymethyl-                                                              cellulose   100 ± 6                                                                               100 ± 5                                                                              100 ± 7                                      ______________________________________                                          *Reported as a percentage of serum cholestrol or serum triglyceride level      as a control + or - the standard deviation.                              

TESTING OF HYPERLIPIDEMIC MICE

A group of six CF¹ male mice (about 25 g) were placed on a commercial diet (U.S. Biochemical Corporation Basal Atherogenic Test Diet) which produced a "hyperlipidemic" state. That is, the average serum cholesterol level in the group of treated mice was raised from 122 to 375 mg percent and triglyceride levels were raised from 137 to 367 mg/dL.

Upon reaching these hyperlipidemic levels, the mice were administered Compounds A, J, M and N in a concentration of 20 mg/kg/d [LD₅₀ value in mice as single injection IP>500 mg/kg for these compounds] intraperitoneally for 14 days while continuing the hyperlipidemic diet. On Day 12, serum cholesterol and serum triglyceride levels were measured in accordance with the procedure of Example 6. The following results were obtained:

                  TABLE 2                                                          ______________________________________                                                     Percent of Control                                                 Compound    Serum Cholesterol                                                                             Serum Triglyceride                                  ______________________________________                                         A           41             40                                                  J           46             49                                                  M           46             54                                                  N           50             46                                                  Diet-Hyperlipidemic                                                                        100            100                                                 ______________________________________                                    

SERUM TESTING OF NORMAL RATS

A test solution of Compounds A, F, J, M, N and O were suspended in an aqueous solution of 1% CMC, homogenized and administered orally to six Sprague-Dawley male rats, which each weighted approximately 350 grams. Administration of the compounds was by an intubation needle. The rats were each fed with 20 milligrams of Compounds A, F, J, M, N and O per kilogram of body weight per day for 14 days. Similarly, six Sprague-Dawley male rats of approximately the same weight (that used for testing F weighed approximately 160 grams) were fed similar volumes of the same aqueous 1% CMC solution without the active agents, also orally, administered by intubation needle. In addition, as a control, a similar group of six male Sprague-Dawley rats were untreated.

On Days 7 and 14, blood was obtained from each of the rats of the three groups by tail vein bleeding. The blood obtained was separated by centrifugation for three minutes. Serum cholesterol and triglyceride levels were determined in accordance with the procedure of Example 6. The following results were obtained:

                  TABLE 3                                                          ______________________________________                                                    Percent of Control                                                             Serum Cholestrol                                                                           Serum Triglyceride                                      Compound     Day 7    Day 14   Day 7  Day 14                                   ______________________________________                                         A            89       69       62     48                                       F            77       66       87     81                                       J            59       60       61     52                                       M            70       36       36     54                                       N            71       67       61     53                                       O            84       60       82     77                                       1% Carboxymethyl                                                                            100      100      100    100                                      cellulose                                                                      ______________________________________                                    

FORMULATIONS A. Tablet

    ______________________________________                                         Ingredient          Amount per tablet                                          ______________________________________                                         Active Compound     150.0    mg                                                Lactose             100.0    mg                                                Corn Starch         15.0     mg                                                Magnesium stearate  1.0      mg                                                ______________________________________                                    

The active compound is finely ground and intimately mixed with the powdered excipients (lactose, corn starch, and magnesium stearate). The formulation is then compressed in a die to produce the tablet.

B. Coated Tablet

    ______________________________________                                         Ingredient          Amount per tablet                                          ______________________________________                                         Core                                                                           Active Compound     150.0    mg                                                Corn Starch         25.0     mg                                                Magnesium stearate  2.0      mg                                                Coating                                                                        Lactose             200.0    mg                                                Corn Starch         50.0     mg                                                Gelatin             10.0     mg                                                ______________________________________                                    

The active ingredient and starch are granulated with water and dried. Magnesium stearate is added to the dried granules Lactose and starch are granulated with 10% w/v aqueous solution of gelatin and dried. Magnesium stearate is added to the dried coating granules The granulated core is compressed with the granulated coating in a conventional compression molding press.

C. Capsule

    ______________________________________                                         Ingredient         Amount per Capsule                                          ______________________________________                                         Active Compound    150.0     mg                                                Lactose            200.0     mg                                                Magnesium stearate 10.0      mg                                                ______________________________________                                    

The finely ground active compound is mixed with the powdered excipients and packed into a two part gelatin capsule

D. Suspension

    ______________________________________                                         Ingredient            Amount per mL                                            ______________________________________                                         Active Compound       75.0    mg                                               Sodium lauryl sulfate 25.0    mg                                               Hydroxypropylmethylcellulose                                                                         100.0   mg                                               Sucrose               50.0    mg                                               Flavor and Color      q.s.                                                     Water                 q.s. 1.0                                                                               mL                                               ______________________________________                                    

The sodium lauryl sulfate, hydroxypropylmethylcellulose, flavor and color are triturated with the active compound This mixture is then blended with 0.5 ml water and sucrose, and additional water is added to make the total volume 1.0 ml of suspension.

The hypolipodemic compounds of the present invention when administered to mammals provide for a significant increase in the HDL cholesterol content (Table 4), coupled with a desirable reduction of the LDL cholesterol content Furthermore, the very low density lipoprotein, which generally is high in triglyceride and neutral lipid content, and which carries these lipids to the tissues from the liver, is markedly reduced by the agents.

                  TABLE 4                                                          ______________________________________                                         The cholesterol content of serum lipoprotein                                   of Sprague-Dawley Rats treated                                                 orally for 14 days at 20 mg/kg/day                                             with compounds A,F,J,M,N and O is tabulated in Table 4.                                 Percent of Control                                                             VLDL                  HDL                                                      cholesterol                                                                            LDL cholesterol                                                                              cholesterol                                     ______________________________________                                         Control 1% 100       100           100                                         CMC compound                                                                   A          44        74            441                                         F          59        78            141                                         J          98        43            194                                         M          71        67            340                                         N          50        87            409                                         O          27        78            113                                         ______________________________________                                     

We claim:
 1. A method for controlling hyperlipidemia in mammals which comprises administering to a mammal an effective amount of a compound having hypolipidemic activity and the structural formula: ##STR8## wherein R¹ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl, a substituted phenyl, cyano, phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;R² is ##STR9## R³ and R⁴ can be the same or different and are each the same as R¹ ; R⁵, R⁶ and R⁷ can be the same or different and are each hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₁ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹, with the proviso that R⁵ and R⁶ are not both aromatic; R⁸ is hydrogen, a C₁ to C₅ alkyl, a C₄ to C₁₀ cycloalkyl, --CO--R⁹, or --Y--CO--R⁹ ; R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ H₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; R¹² is --CO, --CHOH, --CS, --CHSH, or a C₁ to C₄ alkylene group; and Y is a C₁ to C₁₀ alkylene or substituted alkylene; or the pharmaceutically acceptable salts, or mixtures thereof.
 2. The method of claim 1 whereinR² is ##STR10## R³ and R⁴ can be the same or different and are each the same as R¹ ; R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; and Y is a C₁ to C₁₀ alkylene or substituted alkylene; or the pharmaceutically acceptable salts, or mixtures thereof.
 3. The method of claim 2 wherein R¹ is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R³ and R⁴ may be the same or different and are each selected from the group consisting of hydrogen, alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms, and N-phenylcarbamoyl.
 4. The method of claim 3 wherein the compound having hypolipidemic activity is selected from the group consisting of:4-phenyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1-N-phenylcarbamoyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1-ethoxycarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione, 4-(4-n-butyl)-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-I,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione, 4-methyl-1,2,4-triazolidine-3,5-dione, and 4-phenyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione 4-(4-chlorophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-nitrophenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-benzoyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-n-butyl-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione or pharmaceutically acceptable salts or mixtures thereof.
 5. The method of claim 1 whereinR² is ##STR11## R⁵ and R⁶ can be the same or different and are each hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹, with the proviso that R⁵ and R⁶ are not both aromatic; R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ H₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; and Y is a C₁ to C₁₀ alkylene or substituted alkylene; and the pharmaceutically acceptable salts, and mixtures thereof.
 6. The method of claim 5 whereinR¹ is selected from the group consisting of phenyl and substituted phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R⁵ and R⁶ may be the same or different and are each selected from the group consisting of hydrogen or alkoxycarbonyl wherein the alkoxy group has rom 1 to 5 carbon atoms.
 7. The method of claim 1 whereinR² is ##STR12## R⁷ is a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl, a alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹ ; R⁸ is hydrogen, a C₁ to C₅ alkyl, a C₄ to C₁₀ cycloalkyl, --CO--R⁹, or --Y--CO--R⁹ ; R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substituted cycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; R¹² is --CO; and Y is a C₁ to C₁₀ alkylene or substituted alkylene; or the pharmaceutically acceptable salts, or mixtures thereof.
 8. The method of claim 7 wherein R¹ is selected from the group consisting of phenyl, halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; R⁷ is an alkoxy carbonyl wherein the alkoxy group has from 1 to 5 carbon atoms; and R⁸ is hydrogen or a C₁ to C₅ alkyl.
 9. The method of claim 8 wherein the compound having hypolipidemic activity is selected from the group consisting of:3-phenyl-6-ethoxycarbonyl-1,3,5-triazine-2,4(1H,3H)-dione; and 3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-triazine-2,4(1H,3H)-dione; and pharmaceutically acceptable salts and mixtures thereof.
 10. A method for controlling hyperlipidemia in mammals which comprises administering to a mammal an effective amount of a compound having hypolipidemic activity and the structural formula: ##STR13## wherein R¹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or a substituted phenyl, phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;R² is ##STR14## R³ and R⁴ can be the same or different and are each the same as R¹ ; R⁵, R⁶ and R⁷ can be the same or different and are each hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₁ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenalkyl, --CO--R⁹, or --Y--CO--R⁹, with the proviso that R⁵ and R⁶ are not both aromatic; R⁸ is hydrogen, a C₁ to C₅ alkyl, --CO--R⁹, or --Y--CO--R⁹ ; R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, or --NHC₆ H₅ ; R¹² is --CO, --CHOH, --CS, --CHSH, or a C, to C₄ alkylene group; and Y is a C₁ to C₅ alkylene or substituted alkylene; or the pharmaceutically acceptable salts, or mixtures thereof.
 11. The method of claim 10 wherein R² is ##STR15##
 12. The method of claim 10 wherein R² is ##STR16##
 13. The method of claim 10 wherein R² is ##STR17##
 14. A method for controlling hyperlipidemia in mammals which comprises administering to a mammal an effective amount of a hypolipidemically active compound selected from the group consisting of:3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione; and 3-phenyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione; 3-(4-methoxyphenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione; 3-n-butyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione; 3-phenyl-6-methoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione; or pharmaceutically acceptable salts or mixtures thereof. 